Migraine is a common neurological disorder that shows evidence of a significant genetic contribution. However, the genes underlying the predisposition to develop migraine have remained elusive. Although the identification of mutations in a calcium channel gene in a rare, Mendelian form of migraine offered the first insight into potential mechanisms as a complex phenotype that is likely polygenic in origin, candidate gene approaches have not generally proven useful in the search for the genes involved in common migraine. The aims of this proposal are directed toward the identification of major contributing loci involved in migraine susceptibility using the Finnish population. The search for genes predisposing to complex traits is a potentially arduous task, however, the genetically well-characterized population will afford a distinct advantage for initial locus identification that will make the search for the genes predisposing to migraine a more realistic task. It is hypothesized that the predisposition to migraine in a population like Finland is influenced by a subset of loci. The large study sample from this population will improve the ability to detect these loci. A genome-wide scan strategy will be employed to identify susceptibility loci using both a large sample of Finnish migraine families and affected sib-pairs. Statistical simulation studies of the proposed sample suggest that the study material is sufficient to detect major genes predisposing to migraine. Once suggestive evidence for a susceptibility locus has been detected, special statistical strategies including allelic association and shared haplotype analysis will be used in sub-isolates and in families with common ancestors to restrict and confirm the locus. High-resolution physical maps of the candidate regions will be made followed by search for positional candidate genes within the restricted region. Candidate genes will be scrutinized for sequence variations, potentially involved in migraine predisposition. The second hypothesis is that the loci contributing to migraine susceptibility within the isolate are also contributing in a more genetically heterogeneous population. This is supported by findings in other complex diseases, which indicate that the same predisposing loci are detected in genetic isolates as in more mixed populations. Thus, loci identified from the genome scan in the genetic isolate will be examined in multiplex migraine families from Southern California to determine whether the same loci are contributing in the broader population.